The neurotransmitter 5-hydroxytryptamine (serotonin), acting through its binding to a family of receptors, has been implicated in the regulation of a wide variety of biological responses including mood, temperature regulation, pain perception, feeding, sleeping, and learning and memory. Aberrant regulation serotonergic-mediated signaling is also believed to play a critical role in a number of disease processes including affective disorders, migraine, schizophrenia, and cognition processes. In addition, many compounds that are used therapeutically interact with the serotonergic system either through direct interaction with serotonergic receptors or through proteins that modulate serotonin synthesis, reuptake, and breakdown.
The 5-HT6 receptor is expressed selectively in the central nervous system and is likely to be involved in mediating the actions of serotonin in many of these processes (Mol. Pharm. 1993, 43, 320-327). Disruption of 5-HT6 receptor expression, or blockade of 5-HT6 receptor signaling, produces a behavioral syndrome that is reversed by centrally-acting muscarinic antagonists, suggesting that the 5-HT6 receptor is involved in the negative regulation of acetylcholine-mediated neurotransmission (JPET 1995, 274, 173-180; Behav. Brain Res. 1996, 73, 245-248; British J. Pharm. 1999, 126, 1537). Patients with Alzheimer's disease exhibit a gradual loss of cognitive ability that correlates with a decrease in cholinergic neurotransmission. It is anticipated that a selective 5-HT6 receptor antagonist will improve cognitive function in Alzheimer's disease patients by enhancing cholinergic signaling.
Consistent with this hypothesis, preliminary evidence suggests pharmacological blockade of 5-HT6 receptors results in an increased ability of animals to perform in cognition models (British J. Pharm. 1999, 127, 21P; British J. Pharm. 1999, 127, 22P). Compounds which have a selective affinity to 5-HT6 receptors may therefore be suitable for the treatment and prevention of central nervous disorders such as psychoses, schizophrenia, manic depression (Roth, R. L. et al., J. Pharmacol. Exp. Ther. 1994, 268, 1403-1410), depression (Sibley, D. R. et al., Mol. Pharmacol. 1993, 43, 320-327), neurological disorders (Bourson, A. et al., J. Pharmacol. Exp. Ther. 1995, 274, 173-180; Ward, R. P. et al., Neuroscience 1995, 64, 1105-1110), memory disorders, Parkinson's disease, amyotrophic lateral sclerosis, Alzheimer's disease and Huntington's chorea (Sleight, A. J. et al., Neurotransmissions 1995, 11, 1-5). Therefore, based upon the localization of 5-HT6 receptors in the brain, and the wide variety of responses regulated by serotonin, there appears a need to discover novel small molecule 5-HT6 antagonists in order to treat a number of human disorders.
European Patent Application EP 0 941 994 A1, published Sep. 15, 1999, discloses pyrazolopyrimidines and pyrazolotriazines having a selective affinity to 5-HT6 receptors, of the general formulae I-A and I-B shown below: which are suitable for the treatment and prevention of central nervous system disorders. For formulae I-A and I-B, R1 is phenyl, optionally substituted by one or more lower alkyl, halogen, lower alkoxy, tolyl, pyridyl, napthyl or thiophenyl; R2 is hydrogen, lower alkyl, lower thioalkyl, or hydroxy-lower alkoxy; R3 is amino, lower alkylamino, di-lower-alkyl-amino, piperazinyl, optionally substituted by one or more lower alkyl, benzyl, phenyl or hydroxy-lower-alkyl, morpholinyl, imidazolyl, (CH3)2N(CH2)nNH—, (CH3)2N(CH2)nO— or morpholinyl-(CH2)nO— in which n is 2 or 3; R4 is hydrogen, lower alkyl or hydroxy-lower alkyl; R5 is hydrogen, halogen, lower alkyl, C3-C6-cycloalkyl, lower-alkyl-lower-alkoxy, hydroxy-lower-alkyl-lower-alkoxy, (CH3)2N(CH2)nNH—, piperazinyl, optionally substituted by lower alkyl, methyl-piperazinyl, optionally substituted by lower alkyl, morpholinyl, methyl-morpholinyl, di-lower-alkylamino or di-lower-alkylamino-lower-alkyl, or R4 and R5 together are —(CH2)m— or CH2—S—CH2— wherein m is 3 or 4 as well as their pharmaceutically acceptable salts.
U.S. Pat. No. 5,990,105, issued Nov. 23, 1999, to Bos et al. and European Patent Application No. EP 0 930 302, published Jul. 21, 1999, disclose benzosulfone derivatives useful in treating central nervous system disorders of the general formula: wherein R1 is hydrogen; R2 is hydrogen, trifluoromethyl or lower alkyl; R3 is hydrogen or amino; or R1 and R2 or R3 and R2 taken together are —CH═CH—CH═CH—; Z is pyrimidin-4-yl, pyridin-4-yl, pyridin-2-yl or phenyl; R4, R5 are each independently hydrogen, lower alkyl, trifluoromethyl, halogen, lower alkoxy, nitrilo, amino, lower alkyl-amino, di-lower alkyl-amino, piperazinyl, morpholinyl, pyrrolidinyl, vinyl, C3-C6 cycloalkyl, C3-C6 cycloalkenyl, t-butylethinyl, hydroxyalkylethinyl, phenylethinyl, napthyl, thiophenyl, or phenyl, which may be substituted by halogen, lower alkoxy, lower alkyl, trifluoromethyl or nitro, or a group —NH(CH2)nNR6R7, —N(CH3)(CH2)nNR6R7, —NH(CH2)n-morpholin-4-yl or —NH(CH2)nOH; n is 2-4; R6 and R7 are each independently hydrogen or lower alkyl, and pharmaceutically acceptable salts thereof.
PCT Application No. WO 0037452, published Jun. 29, 2000, discloses sulfonyloxazolamines useful in treating conditions implicating the 5-HT6 receptor of the following general formula: wherein R1 and R2 are each independently hydrogen, A, —(CH2)n—Ar, or C2-C6 alkenyl; or R1 and R2 taken together represent a mononuclear saturated heterocycle with one to two heteroatoms; Z is hydrogen, A, CF3, NO2, halogen, hydroxy, OA, NH2, NHA or NA2; A represents C1-C6 alkyl; and Ar is Z-monosubstituted or Z-disubstituted phenyl.
The foregoing disclosures do not teach or suggest the novel pyridopyrimidine derivatives of the present invention. The novel compounds of the present invention display 5-HT6 receptor activity.